Core Insights - Lung cancer is the most common malignant tumor globally and the leading cause of cancer-related deaths, with non-small cell lung cancer (NSCLC) accounting for over 85% of cases. Despite advancements in clinical management, the 5-year overall survival rate for NSCLC patients has only increased from 15% to 25% [2] - Immune checkpoint inhibitors (ICIs), such as PD-1 and PD-L1 inhibitors, have transformed the treatment landscape for NSCLC. However, the objective response rate (ORR) for unselected NSCLC patients receiving ICI treatment is only 10%-30%, with some patients experiencing accelerated disease progression or early death [2] - A new study identified a circRNA signature (circRNA-Sig) consisting of 11 circRNAs that can predict the response to immunotherapy in advanced NSCLC, potentially guiding clinical treatment [3][8] Summary by Sections CircRNA and Cancer - CircRNA is associated with dysregulated RNA expression in cancer and has potential as a biomarker for predicting responses to ICIs [3] Research Findings - The research team analyzed circRNA expression profiles from 891 advanced NSCLC patients in the OAK and POPLAR clinical trials, identifying significantly differentially expressed circRNAs [4] - A predictive model was constructed using machine learning, which was validated and revealed key circRNAs that may influence the efficacy of NSCLC immunotherapy [4] CircRNA-Sig Model - The circRNA-Sig model demonstrated an area under the curve (AUC) of 0.71 in the OAK trial and 0.67 in the POPLAR trial for predicting the efficacy of atezolizumab [5] - Survival analysis indicated that patients with low circRNA-Sig scores benefited significantly more from ICI treatment compared to chemotherapy (HR=1.347), while high-score patients showed no significant difference [5] - Enrichment analysis suggested that low-score patients exhibited an activated tumor immune microenvironment, indicating a mechanistic link between circRNA and ICI treatment sensitivity [5] Clinical Application - The circRNA-Sig model, validated across two large clinical trial cohorts, offers a new stratification tool for NSCLC patients undergoing atezolizumab treatment, enhancing personalized treatment strategies [8]

Core Viewpoint - The in vivo CAR-T field has rapidly evolved over three years, marked by significant acquisitions and clinical advancements, culminating in major deals such as AbbVie’s $2.1 billion acquisition of Capstan Therapeutics and BMS’s $1.5 billion acquisition of Orbital Therapeutics [3][4]. Group 1: Acquisitions and Market Activity - AbbVie announced the acquisition of Capstan Therapeutics for $2.1 billion in cash, highlighting the growing interest in in vivo CAR-T therapies [3]. - BMS acquired Orbital Therapeutics for $1.5 billion, expanding its portfolio into the in vivo CAR-T cell therapy space [4]. - These acquisitions reflect a broader trend of increasing investment and collaboration in the CAR-T sector, indicating a robust market outlook [3][4]. Group 2: Technological Advancements - BMS's acquisition of Orbital enhances its cell therapy research platform, focusing on a potential best-in-class therapy aimed at autoimmune diseases [6]. - The therapy OTX-201, developed by Orbital, is in the pre-IND research stage and is expected to enter clinical trials in the first half of 2026 [6]. - OTX-201 utilizes optimized circular RNA (circRNA) to generate CAR-T cells in vivo, targeting CD19 to treat B-cell driven autoimmune diseases [7]. Group 3: Research and Development Focus - Orbital Therapeutics aims to develop next-generation RNA drugs that reprogram cells to treat diseases at their source, offering a simpler and safer alternative to current CAR-T therapies [10]. - The company’s platform integrates circRNA, linear RNA, targeted delivery systems, and AI-driven design to create durable and programmable therapies [10]. - In addition to autoimmune diseases, Orbital is also exploring in vivo CAR-T therapies for cancer and developing next-generation mRNA vaccines [12].

Core Insights - The article discusses the role of circular RNA (circRNA) in gene expression regulation, highlighting its importance in various biological processes and diseases, particularly cancer [2][8]. Group 1: CircRNA Mechanism and Function - Pre-mRNA reverse splicing leads to the production of circRNA, which shares nearly identical sequences with linear RNA but differs at the back-splicing junction (BSJ) [2]. - CircRNA plays significant roles in gene expression regulation, including transcription modulation, mRNA splicing interference, acting as "sponges" for miRNA or proteins, influencing translation, and even being translated into peptides [2]. - High-expression circRNA has been linked to maintaining quiescent hematopoietic stem cells, regulating cell growth and cancer progression, affecting brain function and neuronal development, and modulating innate immune responses [2]. Group 2: Research Findings on circMAN1A2 - A study published by Fudan University identified a circRNA, circMAN1A2(2,3,4,5), that is highly expressed in tumors and regulates colorectal cancer (CRC) development through RNA-RNA interactions [3][5]. - The research team analyzed the variable circularization (AC) patterns across multiple cell lines and CRC tissues, identifying the primary expressed circRNA at each AC gene locus [5]. - CircMAN1A2(2,3,4,5) enhances the stability of CENPB mRNA by interacting with its 3' untranslated region (3' UTR), and inhibiting this interaction can suppress CRC progression [7][8].